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Animal Models and the Future of Psychiatric Research

"Few
medicines, in the history of pharmaceuticals, have been greeted with
as much exultation as a green-and-white pill containing 20 milligrams
of fluoxetine hydrochloride — the chemical we know as Prozac"
wrote Columbia University Assistant Professor of Medicine Siddhartha
Mukherjee in a recent New York Times editorial on antidepressant
efficacy. As Dr. Mukherjee points out, the rise of antidepressants over the
past several decades has been swift and staggering. A recent CDC study found that antidepressants are the most commonly prescribed
drug for Americans between 18 and 44 years of age, with 11% of
Americans over the age of twelve utilizing such medications.

Original image from the Global Information Exchange Network

In light of such
overwhelming usage rates, one would think that pharmaceutical
companies would be falling over themselves to invent the next
antidepressant superdrug. As it turns out, however, exactly the
opposite trend is emerging. Pharmaceutical giants AstraZeneca and
GlaxoSmithKline recently cut funding for new psychiatric drugs,
leading psychiatrists David Nutt and Guy Goodwin to lament that "The
well-reported pull-out of pharmaceutical companies from neuroscience
research that has occurred in the past year is a major concern... the
withdrawal of research resources is a withdrawal of hope for patients
and their families."

One popular
explanation for pharmaceutical disinterest in new antidepressant
drugs stems from what Dr. Steven Hyman has called a surfeit of
"refried serotonin" - that is, the continual redesign of
antidepressant drugs that affect levels of monoamine
neurotransmitters such as serotonin and norepinephrine in essentially
similar ways.
While this paradigm has led to the development of useful
antidepressant drugs (Lexapro, Paxil, etc.), Hyman argues that
the great advances of recent decades have been in safety and
tolerability, but not in efficacy, which may have peaked in the
1950s. Given that only one third of patients fully recover from
depression on the current generation of antidepressants, it's clear
that a need for more effective therapies persists.

Are antidepressants
based on altering synaptic levels of serotonin and norepinephrine the
best we can do, or are there new drugs, yet to be discovered, that
may revolutionize the treatment of depression? Some have interpreted
pharmaceutical funding cuts as indicative of an over-reliance on
drugs in the treatment of psychiatric disorders and have suggested
increased emphasis on non-pharmacological treatments such as
psychotherapy; others, however, have called for the development of new methods and
paradigms within pharmacology as a means to develop more effective
psychiatric drugs. With Dr. Steven Hyman's visit to Emory to accept the Neuroscience and Ethics Award,
we had the opportunity talk to one of the most respected individuals
in the field about future research directions in psychopathology.

Moving Beyond
Animal Models

Dr. Hyman began by
criticizing reliance on animal-based assays that were originally
developed to produce new antidepressant drugs that acted like older
drugs. The classic "forced swim" and "tail suspension"
tests were developed based on antidepressant drugs discovered in the
1950s. In
the forced swim test, rats are placed in a water-filled cylinder from
which they cannot escape. Researchers found that rats pretreated with
certain antidepressants will attempt to swim for longer periods of
time before giving up. Similarly, rats suspended by the tail and given an antidepressant will struggle for longer in comparison to rats which are not given an antidepressant. Because these assays were worked out using
antidepressants already known to work in humans, and because they
successfully predicted the efficacy of similar antidepressant
compounds, they became standard tools in both academic and industry
labs.

Hyman expressed concern on several fronts:

"First, these are 'black box
assays,' not disease models. As a result they may have limited
predictive power and may actually screen out potentially useful
drugs. Second, they are not even good models of what antidepressants
do in humans. In these assays, antidepressants are active following
a single dose, whereas in humans therapeutic responses required
weeks. At a minimum this should remind us that there is much that we
do not know.”

He added that these screens have invaded basic
academic research. Investigators may laboriously investigate the
function of a gene by knocking it out in the mouse genome or through
injecting it into specific brain regions using a viral vector. They
will then use forced swim or tail suspension to argue that their
mouse may be a depression model, using the term “behavioral
despair” to describe rodents who fail to swim or struggle. This,
said Hyman, is “an anthropomorphism that behavioral pharmacologists
use to deceive themselves about our continuing difficulty of modeling
depression in animals.”

Not the same thing.Original image from drugdiscoveryopinion.com

Moreover, many,
including Dr. Alan Schatzberg, a former Chairman of the Department of
Psychiatry at Stanford University's School of Medicine, have argued
that animal models for depression simply cannot model the cognitive
and emotional aspects of depression that are central to human
experience.
Insofar as animals do not feel guilt or hopelessness, researchers
such as Dr. Schatzberg argue that animal models cannot measure the
same disease processes that exist in depressed humans.

Dr. Hyman noted that
animal models have yielded clear success in studying highly penetrant
monogenic disorders such as Rett Syndrome and Fragile X syndrome, as
well as the functions of circuits that are highly conserved in
evolution such as "basic emotions of fear and reward."
However, he also noted that these models have had limited utility to
date in studying common mental disorders, which are generally
polygenic, heterogeneous, and involve circuits in the prefrontal cortex
that are not well modeled in rodents.

Animal models have
proliferated largely as an alternative to testing novel
pharmaceuticals on humans, a practice which holds potentially
problematic ethical implications. As a result, a difficult and important question emerges: how can testing procedures be refined to
produce effective psychiatric medications without putting humans at
excessive risk?

New Directions in
Human Research

Dr. Hyman suggested
a number of novel methods that he believes could reinvigorate
research into psychopathology and therapeutics. One possibility,
which he noted is "still almost
as much
science fiction
as real,"
is based on the rapidly progressing technology of reprogramming
peripheral cells such as human fibroblasts into neurons. Future work
in this area may be capable of creating replicable neurons of
specific types and assembling them into circuits, perhaps on a chip.
As knowledge of the genetics of mental disorders advances,
disease-risk versions of genes could be engineered into such cells
and then compared to patient cells. Dr. Hyman suggested that study of biochemical and cellular phenotypes may yield therapeutic benefits that exceed those produced by studies of rodent behavior.

Dr. Hyman also saw
promise in innovative forms of "human experimental biology"
that combine treatment interventions such as deep brain stimulation
with brain imaging to understand underlying circuits in
neuropsychiatric disorders. In particular, he praised Emory
researcher Dr. Helen Mayberg for continuing her research on deep brain stimulation (DBS) as a
treatment for depression, even after DBS had demonstrated therapeutic
benefit:

"I
think I
have great
respect for
what Helen
Mayberg and
the group
are doing
here because
they didn't
stop at
saying, well,
this works,
meaning it
improves the
Hamilton Depression rating
in otherwise
treatment
refractory
patients 60%
of the
time. They've
also followed
it up
by --
with very
inventive imaging
approaches to
see what
circuits are
involved. I
think that
within the
bounds of
careful, ethical
and safety considerations
we must learn from humans what we cannot readily learn from animals.”

More broadly, Dr.
Hyman emphasized the need to think creatively about novel ways to
approach long-standing research problems. He advocated convergent
interdisciplinary approaches to problems and avoidance of “cottage
industries” that lead nowhere. In particular, Dr. Hyman noted the
hundreds of genetic associations studies that have been done on
genetic variants such as the length polymorphisms in the serotonin
transporter gene, which have already been identified as the target of
a host of moderately efficacious drugs.

Neuroethical
Implications

Research with human
subjects raises a number of unique problems. The first is a problem
of external validity: current trials with humans have been criticized
on a number of grounds, including excessively stringent exclusion criteria and selective publication of studies demonstrating positive results.
The second is an ethical problem: research with human subjects
involves issues of safety, informed consent, and possible
exploitation of vulnerable populations such as prisoners or children.
These and similar concerns have led some, such as the Alliance for Human Research Protection, to oppose past efforts to expand drug
experimentation on humans.

More broadly, the
insufficiency of current research paradigms in psychiatric drug
development raises questions about the fundamental nature of
psychiatric practice. Are mental disorders best understood as
physical illnesses like any other, discrete neurological deficits
that can be cured through the use of appropriate medications, or are
they what some psychiatrists have termed "problems in living,"
more loosely defined constructs that don't necessarily imply
biological solutions?

Robert Whitaker, a
vocal critic of the biomedical paradigm in psychiatry, suggests that
funding cuts for new pharmaceuticals may have a "silver lining":
"it is possible that the drug tsunami that has swept over our
society will begin to ebb, and this will provide our society an
opportunity to rethink its psychiatric care." For Whitaker, there is little hope that new research methods will
substantially contribute to our capacity to treat mental illness, and
we would be wise to reconfigure our understanding of mental illness
to emphasize aspects of "wellness" rather than "disease."
Such claims imply that work with animals is likely to yield little
benefit in the treatment of depression, as animals cannot model
uniquely human aspects of depression such as guilt and hopelessness.
Whitaker's arguments are also likely to be met with skepticism in
research circles, where the disease model of mental illness still
prevails. Whatever new paradigms are adopted within psychiatric
research, then, are likely to hold significant implications not only
for what sorts of treatments are developed, but also for our
understanding of what it means to be "normal" and
"disordered" more generally.

Want to cite this post?
Gordon, R. (2012). Animal Models and the Future of Psychiatric Research. The Neuroethics Blog. Retrieved on
, from http://www.theneuroethicsblog.com/2012/06/animal-models-and-future-of-psychiatric.html

Comments

Thanks for this thoughtful blog. You cover a lot - from the usefulness of animals models, to "human experimental biology," to whether mental illness should be conceptualized as physical illnesses or "problems of living."

In regards to the last point, my position has been that we need to approach mental illnesses as BOTH physical illnesses and social problems or problems of living. Do you think the two approaches can be pursued at the same time or are they inherently opposed to each other?

I agree that both approaches can absolutely be pursued at the same time. I think what's important isn't whether depression is "really" a brain disease (or "really" a social/existential problem) but rather which attribution is most likely to produce positive results in a particular case.

If, hypothetically, someone invented a new drug that was 95% effective at ameliorating depression without incurring significant side effects, I think that depression would be, for all intents and purposes, a "brain disorder." If you take the 33% efficacy of current antidepressants at face value, though, I think you have to (at least provisionally) be a little more flexible in what you take "depression" to mean.

That's why I think new psychiatric drug development is so important in thinking about what it means to be "mentally disordered": in some ways, I think the "brain disease" model as much hypothesis than fact, and the development of a new, supereffective antidepressant would go a long way towards supporting the latter characterization.